Comprehensive Ara-C SNP score predicts leukemic cell intracellular ara-CTP levels in pediatric acute myeloid leukemia patients.

Abstract

Cytarabine (Ara-C), a mainstay of acute myeloid leukemia (AML) treatment, is a prodrug requiring activation to ara-CTP for its antileukemic activity. Aim of this study was to evaluate impact of genetic variants in the key genes involved in ara-C metabolism on the leukemic cell intracellular levels of ara-CTP. We investigated SNPs in 14 ara-C metabolic-pathway genes,for association with intracellular ara-CTP levels, in leukemic cells obtained post-initiation of cytarabine infusion in pediatric AML patients (n = 68). Nine SNPs were significantly associated with leukemic cell intracellular concentration of ara-CTP.A comprehensive ara-CTP-SNP-score (ACSS) was further developed from top four SNPs identified in regression model. Patients were classified into three groupsbased on ACSS: high-ACSS (score>0), intermediate-ACSS (score=0) and low-ACSS (score<0). ACSS designation was significant predictor of intracellular ara-CTP levels (p=0.00012), suggesting a cumulative or synergistic effect of the significant SNPs. ACSS score designation holds promise in definfing ara-C dose. Validation of the clinical utility of ACSS score in other independent cohorts will help identification of patients with potentially lower or higher levels of the ara-CTP in leukemic cells,thereby opening up opportunities for dose management to reduce toxicity and enhance efficacy.